Coronavirus pneumonia in kidney transplant recipients: current evidence from own clinical experience

The course and management of coronavirus infection (CI) in patients with severe comorbidity are extremely important scientific and practical issues in the era of COVID-19. Kidney transplant recipients make up one of the most vulnerable groups for CI-associated adverse outcomes. Considering the presence of comorbidities, the optimal pharmacotherapy regimens for CI and its complications have not yet been worked out for these patients. In this article, we present two clinical observations demonstrating typical manifestations of coronavirus pneumonia (CP) in kidney transplant recipients, the COVID-19 diagnostic and verification algorithm, and the therapeutic options used to achieve a favorable outcome of CP and to prevent fatal complications. Our findings confirm that in kidney transplant recipients CP is linked to increased disease severity with rapid progression of lung damage and a high risk of developing systemic complications, including thrombotic microangiopathy. It is shown that compliance with the current recommendations for a rational combination of antiviral, anti-inflammatory, anticoagulant and basic immunosuppressive agents in this group of patients provides good treatment outcomes and prevents kidney transplant failure. Two adverse outcomes in the observed group were due to associated opportunistic infection. Based on our findings and clinical data, we conclude that preemptive therapy with IL-6 inhibitors or colchicine is an effective therapeutic option in kidney transplant recipients.

Common Viral Infections In Children After Kidney Transplantation

Viral infection is a common complication among pediatric kidney transplant recipients, causing significant morbidity and mortality. Sources of viral infection in pediatric transplant recipients include donor allografts, blood products, and latent virus reactivation. Major risks of viral infection include kidney donor-derived, nosocomial and community-acquired infections as well as the immunosuppressive status of recipients. Clinical presentations are variable, ranging from no symptoms to severe disease. Preventive strategies such as immunization and pretransplant-specific viral screening in both donors and recipients are performed before kidney transplantation to identify high-risk recipients. Posttransplant prophylactic strategies include universal prophylaxis and preemptive therapy. Universal antiviral prophylaxis is required for high-risk cytomegalovirus (CMV)-mismatch pediatric recipients. Preemptive therapy requires the administration of sensitive viral surveillance tests to detect subclinical viral infections to optimize individualized immunosuppressive drugs and initiate antiviral therapy. This review summarizes current knowledge regarding common viral infections in children after kidney transplantation, including CMV, BK polyomavirus, Epstein-Barr virus (EBV), and coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Development of a Method of Measuring β-D-Glucan and Its Use in Preemptive Therapy for Invasive Fungal Infections

Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal infections. However, many studies have indicated that antifungals were not necessary for over half of patients, and several detriments of empirical therapy were noted, e.g., antifungals caused adverse reactions, an increase in drug-resistant fungi was a possibility, and medical costs soared. β-D-glucan (BDG) is a component of clinically important fungi such as Aspergillus and Candida. The G-test was developed in Japan as a way to measure BDG in serum using a coagulation factor from the blood of the horseshoe crab. Pre-emptive antifungal therapy based upon serodiagnosis with a BDG or galactomannan assay and CT imaging has been introduced. With pre-emptive antifungal therapy, the prognosis is equivalent to that with empirical therapy, and the dose of the antifungal has been successfully reduced. Measurement of BDG has been adopted widely as a method of diagnosing IFIs and is listed in the key guidelines for fungal infections and febrile neutropenia.

Clinical validation of an in-house quantitative real time PCR assay for cytomegalovirus infection using the 1st WHO International Standard in kidney transplant patients

Introduction: Cytomegalovirus (CMV) is one of the most common agents of infection in solid organ transplant patients, with significant morbidity and mortality. Objective: This study aimed to establish a threshold for initiation of preemptive treatment. In addition, the study compared the performance of antigenemia with qPCR results. Study design: This was a prospective cohort study conducted in 2017 in a single kidney transplant center in Brazil. Clinical validation was performed by comparing in-house qPCR results, against standard of care at that time (Pp65 CMV Antigenemia). ROC curve analysis was performed to determine the ideal threshold for initiation of preemptive therapy based on the qPCR test results. Results: Two hundred and thirty two samples from 30 patients were tested with both antigenemia and qPCR, from which 163 (70.26%) were concordant (Kappa coefficient: 0.435, p<0.001; Spearman correlation: 0.663). PCR allowed for early diagnoses. The median number of days for the first positive result was 50 (range, 24-105) for antigenemia and 42 (range, 24-74) for qPCR (p<0.001). ROC curve analysis revealed that at a threshold of 3,430 IU/mL (Log 3.54), qPCR had a sensitivity of 97.06% and a specificity of 74.24% (AUC 0.92617 ± 0.0185, p<0.001), in the prediction of 10 cells/105 leukocytes by antigenemia and physician's decision to treat. Conclusions: CMV Pp65 antigenemia and CMV qPCR showed fair agreement and a moderate correlation in this study. The in-house qPCR was revealed to be an accurate method to determine CMV DNAemia in kidney transplant patients, resulting in positive results weeks before antigenemia.

Breakthrough Invasive Fungal Infections in Allogeneic Hematopoietic Stem Cell Transplantation

Despite the recent introduction of mold-active antifungal prophylaxis (MAP), breakthrough invasive fungal infections (b-IFI) still represent a possible complication and a cause of morbidity and mortality in hematological patients and allogeneic hematopoietic stem-cell transplantation recipients (HSCT). Data on incidence and type of b-IFI are limited, although they are mainly caused by non-fumigatus Aspergillus and non-Aspergillus molds and seem to depend on specific antifungal prophylaxis and patients’ characteristics. Herein, we described the clinical presentation and management of two cases of rare b-IFI which recently occurred at our institution in patients undergoing HSCT and receiving MAP. The management of b-IFI is challenging due to the lack of data from prospective trials and high mortality rates. A thorough analysis of risk factors, ongoing antifungal prophylaxis, predisposing conditions and local epidemiology should drive the choice of antifungal treatments. Early broad-spectrum preemptive therapy with a lipid formulation of amphotericin-B, in combination with a different mold-active azole plus/minus terbinafine, is advisable. The therapy would cover against rare azole-susceptible and -resistant fungal strains, as well as atypical sites of infections. An aggressive diagnostic work-up is recommended for species identification and subsequent targeted therapy.

Unexpected CMV replication kinetics in CMV- donor seropositive recipient seronegative liver transplant recipients receiving preemptive antiviral therapy

Background Detailed CMV kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+R-) transplant recipients receiving preemptive therapy (PET) have not been fully defined. Methods The study population consisted of PET arm of a randomized CMV prevention trial in D+R- liver transplant recipients. CMV-DNA PCR assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation). Results Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3,350 IU/mL; 25.7% (19/74) of the patients had peak levels &gt; 10,000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had significantly lower rate of recurrent viremia than those without such increase (40%,16/40 vs. 71.8%, 28/39, p=0.004), respectively. Conclusions A majority of D+R- recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance.

Cytomegalovirus-specific T-cell Reconstitution following Letermovir Prophylaxis after Hematopoietic Cell Transplantation

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. We compared polyfunctional CMV-specific T-cell responses in a prospective cohort of allogeneic HCT recipients who received letermovir to controls who received PCR-guided preemptive therapy prior to the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at three months post-HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen specific T-cell subsets (COMPASS). Letermovir use and reduction in viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjusting for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65; whereas CMV shedding rate was associated with greater CD4+ responses to IE-1. In conclusion, our study provides initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly due to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

Survey of HCMV in allogenic and autologous stem cell transplantation by real-time PCR in Kermanshah, west of Iran

Introduction Human Cytomegalovirus (HCMV) is the most important viral pathogen in people undergoing bone marrow transplantation (BMT). HCMV detection in the early stages makes is possible to save the patients’ lives through immediate and timely treatment. The aim of this study was to investigate the status of HCMV using the real-time PCR method in BMT patients in Kermanshah, west of Iran. Methods HCMV monitoring was done in 120 patients who underwent BMT, 38 allogeneic cases and 82 autologous cases, using the ELISA serology test before transplantation. The participants were followed up 100 days after transplantation for HCMV detection in blood samples using real-time PCR. Preemptive therapy started with Ganciclovir and Foscarnet when the viral load was > 200 HCMV DNA copies/ml. Results Despite preemptive therapy, infection recurred in less than 1 month. HCMV recurred more frequently in patients undergoing allogenic transplation versus those receiving autologous transplantation. Recurrence was seen in 5 patients receiving allogenic transplantation. HCMV recurrence occurred in five patients with allogeneic transplantation. Twelve patients undergoing allogeneic or autologous transplantation (83%) and a virus load of > 1000 copies/ml showed HCMV-related symptoms. Three patients died, two due to HCMV-related pneumonia and the other one due to a fungal infection. Conclusion Real-time PCR may be a useful method for quantification and monitoring of HCMV recurrence and may be helpful in choosing more efficient HCMV preemptive treatment in BMT recipients.